Systems and methods for remotely monitoring the cryogenic processing of samples

ABSTRACT

A remote system for monitoring and controlling one or more devices for use in the cryogenic processing of a sample is provided. A remote server capable of transmitting freezing profile data to one or more freezers, transmitting transportation profile data to one or more transportation devices, and transmitting thawing profile data to one or more thawing devices. The remote server is also capable of receiving detected data from the one or more freezers relating to the freezing of a sample in accordance with the freezing profile data, receiving detected data from the one or more transportation devices relating to the transportation of a sample in accordance with the transportation profile data, and receiving detected data from the one or more thawing machines relating to the thawing of a sample in accordance with the thawing profile data.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/463,705 filed on May 23, 2019, which claims the priority benefit ofPCT/GB2017/053532 filed on Nov. 24, 2017 which claims priority benefitof Great Britain Application No. 1620017.2 filed Nov. 25, 2016. Theentire contents of which are hereby incorporated by reference herein.

BACKGROUND

The present techniques relate to systems and methods for remotelymonitoring the cryogenic processing of samples. More particularly, thetechniques relate to systems and methods for remotely monitoring thecryogenic freezing, the cryogenic storing, the cryogenic transportationand the cryogenic thawing of samples.

Cryogenic processing of a sample involves temperatures below −90° C.(−130° F.). The cryogenic freezing of a sample involves reducing thetemperature of the sample to, or below, −90° C. The cryogenic thawing ofa sample involves increasing the temperature of the sample from 90° C.or below. The cryogenic storing and the cryogenic transportation of asample involves maintaining the temperature of the sample at, or below,−90° C. In most instances the cryogenic storing and the cryogenictransportation of a sample involves maintaining the temperature of thesample at the temperature at which it was cryogenically frozen.

Cryogenic processing can be utilised in many different fields, such asregenerative medicine, biobanks, atmospheric microphysics, conservation,assisted reproduction, transgenics, food processing, freeze drying.Cryogenic processing can be used for a variety of products, theseinclude cells and tissues for clinical application for example in thefields of regenerative medicine, transplantation, transfusion andvaccination, where the requirement is to maintain cell viability andfunction on thawing, or tissue integrity and functionality. Cryogenicprocessing can be used can also be used with non cellular materials, forexample with traditional vaccines and for acellular samples forbiobanking.

SUMMARY OF THE INVENTION

The cryogenic processing described herein may be used for the transportof samples such as T cells and haematopoietic cells from patients tocentres which manufacture immunotherapies or gene therapies, or biopsiesfrom the operating theatre to biobanks for long term storage. Thecryogenic processing described herein may also be used to transportmanufactured cell products such as immunotherapies or gene therapiesfrom the site of manufacturing to the patient.

In order to maintain, and confirm, the integrity of a sample at everypoint throughout its processing, from freezing to storage totransporting and to thawing, close monitoring of the sample is required.

According to a first aspect of the present techniques, there is provideda system for remotely monitoring cryogenic processing of a sample.

According to a second aspect of the present techniques, there isprovided a method for remotely monitoring cryogenic processing of asample.

According to a third aspect of the present techniques, there is provideda cryogenic freezer for freezing a sample in accordance with a samplefreezing profile.

According to a fourth aspect of the present techniques, there isprovided a cryogenic thawing machine for thawing a sample in accordancewith a sample thawing profile.

According to a fifth aspect of the present techniques, there is provideda cryogenic transportation device for transporting a cryogenicallyfrozen sample in accordance with a sample transportation profile.

According to a sixth aspect of the present techniques, there is provideda remote server for remotely monitoring cryogenic processing of asample.

According to a seventh aspect of the present techniques, there isprovided a computer program product comprising computer code forperforming any of the methods described herein.

According to an eighth aspect of the present techniques, there isprovided a system for remotely monitoring cryogenic processing of asample.

According to a ninth aspect of the present techniques, there is provideda system for remotely monitoring cryogenic processing of a sample.

According to a tenth aspect of the present techniques, there is provideda system for remotely monitoring cryogenic processing of a sample.

According to an eleventh aspect of the present techniques, there isprovided a system for remotely monitoring cryogenic processing of asample.

According to a twelfth aspect of the present techniques, there isprovided a system for remotely monitoring cryogenic processing of asample.

According to a thirteenth aspect of the present techniques, there isprovided a method for remotely monitoring cryogenic processing of asample.

According to a fourteenth aspect of the present techniques, there isprovided a method for remotely monitoring cryogenic processing of asample.

Preferred features are set out in the appended dependent claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments will now be described with reference to the accompanyingFigures of which:

FIG. 1 schematically illustrates a cryogenic freezer;

FIG. 2 illustrates a predetermined freezing profile;

FIG. 3 illustrates a detected plate temperature during a freezing cycle;

FIG. 4 illustrates a detected sample temperature during a freezingcycle;

FIG. 5 illustrates the predetermined freezing profile of FIG. 2 , thedetected plate temperature of FIG. 3 and the detected sample temperatureof FIG. 4 ;

FIG. 6 schematically illustrates a remote server;

FIG. 7 schematically illustrates a system for monitoring one or morecryogenic freezers;

FIG. 8 illustrates a graph of the detected plate temperature of FIG. 3and the detected sample temperature of FIG. 4 and annotated with“observations”;

FIG. 9 schematically illustrates an overview of the processing of abiological sample;

FIG. 10 schematically illustrates a thawing machine;

FIG. 11 illustrates a thawing profile;

FIG. 12 illustrates a detected sample temperature during a thawingcycle;

FIG. 13 schematically illustrates a system for monitoring one or morethawing machines;

FIG. 14 illustrates the detected sample temperature of FIG. 12 astransferred to the server of FIG. 6 and annotated with “observations”;

FIG. 15 schematically illustrates a storage device;

FIG. 16 schematically illustrates schematically a remote system formonitoring one or more devices for use in the cryogenic processing of asample;

FIG. 17 illustrates a graph of two different sets of detected thawingtemperatures; and

FIG. 18 illustrates a graph of the power required to cool a biologicalsample through the ice formation region.

DETAILED DESCRIPTION

A remote system for monitoring and controlling one or more devices foruse in the cryogenic processing (e.g. freezing, cooling and/or thawing)of a sample is provided. The remote system may use freezing profile dataand/or thawing profile data for the cryogenic processing. A remoteserver is capable of transmitting freezing profile data to one or morefreezers, transmitting storage profile data to one or more storagedevices and/or transportation devices, and transmitting thawing profiledata to one or more thawing devices. The remote server is also capableof receiving detected data from the one or more freezers relating to thefreezing of a sample in accordance with the freezing profile data,receiving detected data from the one or more storage devices and/ortransportation devices relating to the storage and/or transportation ofa sample in accordance with the storage profile data, and receivingdetected data from the one or more thawing machines relating to thethawing of a sample in accordance with the thawing profile data. Thedetected freezing data and/or the detected thawing data may berecorded/stored, and may be provided to a user/third party.

In order to cryogenically freeze a sample, a cryogenic freezer, such asa freezer in the VIA FREEZE range by ASYMPTOTE can be used. FIG. 1schematically illustrates a cryogenic freezer 1. As can be seen fromFIG. 1 , a cryogenic freezer 1 comprises a freezer compartment 28,within which a sample 30 to be frozen may be provided, coupled to a heatremoval unit 32. The freezer 10 also comprises a control module 10comprising at least one processor 12 coupled to at least one memory 18,at least one user interface 14, at least one communications interface26, at least one data store 16, and at least one sensor 20, 22, 24 . . .n. The freezer 10 may also comprise other elements which are notillustrated.

The memory 18 may comprise program memory for storing computer programcode to control the heat removal unit 32 in order to freeze a sample 30as described herein, and working memory for storing data, programs, orinstructions received or processed by the processor 12. The memory 18and/or the data store 16 may comprise a volatile memory such as randomaccess memory (RAM), for use as a temporary memory. Additionally oralternatively, the memory 18 and data store 16 may comprise non-volatilememory such as Flash, read only memory (ROM) or electrically erasableprogrammable ROM (EEPROM).

The processor 12 may comprise processing logic to process data (forexample, data received from the sensors 20, 22, 24, . . . n, programs,instructions received from a user via the user interface 14 etc.) andgenerate output signals in response to the processing. The controlmodule 10 may comprise any suitable circuitry or logic, and may, forexample, comprise any one or more of the following: a field programmablegate array (FPGA), system on chip device, microprocessor device,microcontroller, and one or more integrated circuits. The control module10 is coupled to the heat removal unit 32 in order to control thetemperature in the freezer compartment 28.

The user interfaces 14 may be one or more of a computer screen, a touchscreen, a keyboard, a mouse, speakers, a bar code scanner, a fingerprintscanner etc.

The communication module 26 may be configured to receive data or datasignals from one or more external devices (such as a remote server asdescribed herein). The communication module 26 may be a communicationinterface or unit. The communication module may be configured to receivedata via a wired or wireless network, such as the internet. Thecommunication module may also be configured to transmit data or datasignals to one or more external devices (such as a remote server) via awired or wireless network, such as the internet.

The data store 16 may be configured to store data from the sensors 20,22, 24, . . . n. The data store 16 may be coupled to the at least onecommunication module 26 and the at least one processor 12.

The components of the control module 10 may be a combination of hardwareand software components, all software components, or all hardwarecomponents.

Cryogenic freezers, such as illustrated in FIG. 1 , cryogenically freezea sample in accordance with a freezing profile. It is known that eachsample variation requires its own freezing profile to be predeterminedby a skilled scientist. A freezing profile is determined by a skilledscientist based on numerous factors such as the composition of thesample, the cell type or types used, the size (weight) of the sample,the nucleation temperature, the amount of cryoprotectant used, thecontainer within which the sample is provided etc. Compounds with aprotective impact during cryopreservation are referred to ascryoprotectants. In some embodiments, the cryoprotectant may be selectedfrom dimethyl sulfoxide (DMSO), glycerol, glucose, propylene glycol,polyethylene glycol, sugars, alcohols, sugar alcohols, apoptosisinhibitors, ficoll, polyvinylpyrollidine, or a combination of two ormore of these cryoprotectants, at concentrations ranging from 0 to 100%.

A freezing profile is specific to the factors upon which it isdetermined. For example, a freezing profile which is determined for 2 mlof sample A may be different from a freezing profile determined for 250ml of sample A, or a freezing profile which is determined for 200 ml ofsample A with 10% DMSO may be different from a freezing profiledetermined for 200 ml of sample A with 12% DMSO.

FIG. 2 schematically illustrates an exemplary predetermined freezingprofile for a sample (illustrated using a graph of temperature v'stime). A freezing profile comprises a set of instructions, regardless offormat, which are input into a freezer, and which define the rate ofcooling of the sample during a freezing cycle. A freezing cycle beginsat time t=0 minutes, when a sample is placed in a freezer. In mostinstances, a sample will be between room temperature and the sample'sfreezing point at the beginning of the freezing cycle. A freezing cycleends when the sample has reached the desired temperature, which isdefined in the freezing profile. For example, according to FIG. 2 , thefreezing cycle ends at time t=180 minutes.

A freezing profile may comprise different linear cooling rates (ramps),as well as constant-temperature holding times (dwells) etc. and mayinclude linear and non-linear cooling protocols. As stated above, afreezing profile is predetermined for each sample variety. Whenever asample is to be frozen, which has the same sample composition, samplesize, amount of cryoprotectant, and container etc. as defined in apredetermined freezing profile, then that predetermined freezing profileis required to be programmed into the freezer. According to knownsystems, each predetermined freezing profile is provided to a humanoperator in paper form, normally as part of an instruction manual, andthe human operator is required to enter the predetermined freezingprofile via the user interface 14 at the freezer.

However, since the predetermined freezing profile is entered manually bya user, errors may occur, for example, typographical errors may beentered by the user of the system when copying the predeterminedfreezing profile from the paper version.

As stated above, the freezer 10 comprises at least one sensor 20, 22, 24. . . n. One, or more, of the sensors 20, 22, 24 . . . n comprises atemperature sensor provided to monitor the temperature within thefreezer compartment 28 during a freezing cycle. The temperature sensorsdetect the temperature at one or more different locations within thefreezer compartment 28, such as at the plate within the freezercompartment 28. The temperature is detected during the freezing of asample, in accordance with a predetermined freezing profile, and thedata store 16 stores the detected temperatures together with thelocation of the sensors and/or a sensor ID and the time at which thetemperature was sensed.

FIG. 3 schematically illustrates a detected plate temperature v's timeduring the freezing of a sample in accordance with the predeterminedfreezing profile of FIG. 2 .

In addition to detecting the temperature at different locations withinthe freezer compartment 28, one or more sensors 20, 22, 24 . . . n, canalso be provided to detect the actual temperature of the sample duringthe freezing cycle. The sensors 20, 22, 24 . . . n, detect the actualtemperature during the freezing of a sample, in accordance with apredetermined freezing profile, and the data store 16 stores thedetected temperatures together with the location of the sensor and/or asensor ID and the time at which the temperature was sensed.

FIG. 4 schematically illustrates a detected sample temperature v's timeduring the freezing of the sample in accordance with the predeterminedfreezing profile of FIG. 2 .

FIG. 5 schematically illustrates the predetermined freezing profile ofFIG. 2 , the detected plate temperature of FIG. 3 and the detectedsample temperature of FIG. 4 . As is understood in the art, and asillustrated in FIG. 5 , the actual detected freezing of a sampleachieved by each freezer may vary from the predetermined freezingprofile. Variations can occur as a result of numerous factors, such asthe accuracy of the preparation of the sample. For example, a particularpredetermined freezing profile may require 200 ml of sample A, mixedwith 10% DMSO. However, one user 120, 121, 122, . . . , 12 n mayinadvertently add 195 ml of sample A mixed with 10.5% DMSO, or 202 ml ofsample A mixed with 11% DMSO etc. Variations may also occur as a resultof variations at the freezer, for example a freezers heat removal unit32 may not be functioning as efficiently as possible.

In addition to detecting the actual temperatures during a freezingcycle, one or more sensors 20, 22, 24 . . . n may be provided to detectthe external temperature at the freezer during a freezing cycle. Inaddition, one or more sensors may be provided to detect when the door ofthe freezer is opened, when the door of the freezer is closed, the timeand date at which the door is opened/closed, and/or the duration of timethe door was open.

According to one embodiment, the sensors 20, 22, 24 . . . n detectcontinuously during a freezing cycle. According to another embodiment,the sensors 20, 22, 24 . . . n detect periodically during a freezingcycle.

The sensor data detected by the sensors 20, 22, 24 . . . n relates tothe freezing of a sample in accordance with a freezing profile. Thesensor data detected by the sensors 20, 22, 24 . . . n may comprise oneor more of: the temperature at one or more different locations withinthe freezer compartment 28 during a freezing cycle; the temperature ofthe sample during a freezing cycle; the external temperature at thefreezer during a freezing cycle; freezer door data, such as when thedoor of the freezer is opened and/or closed during a freezing cycle andthe duration of time the door was open for. For each detection, the timeand date of the detection is also recorded together with an indicationof the detecting sensor.

In addition to the sensor data detected by the sensors 20, 22, 24 . . .n, the control module 10 is also capable of detecting and storing otherdata which relates to the freezing of the sample in accordance with thefreezing profile. The other data may comprise freezer data and/or sampledata and/or user data etc. The control module 10 may store freezer datasuch as: a freezer identifier; freezer energy consumption (the energyconsumed by the freezer during the freezing cycle and/or the energyconsumed by different components of the freezer during the freezingcycle); freezer location (the actual location of the freezer and/or thefreezers IP address); freezer alarm data (such as whether an alarm wasactivated at the freezer, for example, a door open alarm, and/or whetherany action was taken in response to the alarm, for example, the door wasclosed). The control module 10 may store sample data such as: a sampleidentifier; sample composition data (such as information regarding thecomposition of the sample); sample size/weight data (such as informationregarding the size/weight of the sample); sample container data (such asinformation regarding the sample container); the predetermined freezingprofile; sample freeze date (such as the date the sample was frozen inaccordance with the freezing profile); sample freeze time (such as thestart time of the freezing cycle, the end time the freezing cycle,and/or the duration of the freezing cycle). The control module 10 maystore user data such as: a user identifier; user observations, discussedin further detail below.

The sensor data detected by the sensors 20, 22, 24 . . . n, as well asthe freezer data and/or sample data and/or user data, all of whichrelates to the freezing of a sample in accordance with a freezingprofile, is of interest to a user. However, the user may not be at thelocation of the freezer, for example, because the user requires datafrom multiple freezers, or because the user is performing a clinicaltrial which requires data from multiple locations. Therefore, thecommunication module 26 may be used to transfer the data to a remoteserver.

FIG. 6 illustrates schematically a remote server 50. The remote server50 comprises at least one processor 52, at least one working memory 54,at least one stored program memory 58, at least one data store 56 and atleast one communication module 60. The remote server 50 may alsocomprise other components which are not illustrated. The components ofthe remote server 50 may be a combination of hardware components andsoftware components, may be all software components, or may be allhardware components,

The remote server is communicatively coupled to at least one freezer.According to one embodiment, the communication module 60 is used toconnect the remote server 50 to at least one cryogenic freezer over anetwork, such as the Internet. The connection may be wired or wireless.The at least one cryogenic freezer is then able to exchange data withthe remote server 50. For example, the at least one cryogenic freezer iscapable of transmitting data to the remote server 50, and the remoteserver 50 is capable of receiving the transmitted data from the at leastone cryogenic freezer. In addition, the remote server 50 is capable oftransmitting data to the at least one cryogenic freezer, and the atleast one cryogenic freezer is capable of receiving the transmitted datafrom the remote server 50.

According to one embodiment, the data which is transferred between thefreezer and the server is encrypted. For example, using a private/publickey pair etc.

A user can access the remote server 50 from any computing device (suchas a laptop computer, a tablet, a smart phone, a personal computer etc.)via a web browser. According to one embodiment, the user may be requiredto log into and have an account at the remote server. Followingconnection to the remote server 50, the user is able to access the datafrom the freezers. According to one embodiment, a data mining processmay be applied to the data gathered at the remote server, in order toextract information and/or patterns from the data which would not havebeen possible without collating of the data.

FIG. 7 illustrates schematically a system for monitoring one or morecryogenic freezers. A plurality of cryogenic freezers 100, 101, 102, . .. , 10 n are illustrated in FIG. 7 . For the avoidance of doubt, aplurality may be any number, including one. Each of the plurality offreezers 100, 101, 102, . . . , 10 n may be provided at the same, or atdifferent locations from the other freezers. Each freezer 100, 101, 102,. . . , 10 n may be operated by a human operator (users 120, 121, 122, .. . , 12 n). In addition, each freezer 100, 101, 102, . . . , 10 n iscommunicatively coupled to a remote server 130. The remote server 130 iscapable of receiving data from the freezers in order to monitor thefreezers as well as transmitting data to the freezers.

As stated above, freezing profiles are predetermined by skilledscientists. The predetermined freezing profiles are then providedtogether with their associated criteria, such as the composition of thesample, the size of the sample, the amount and composition ofcryoprotectant to be added to the sample, the type of container in whichthe sample is to be provided etc., to the remote server 130. Accordingto one embodiment, the remote server 130 transmits the predeterminedfreezing profiles to the plurality of freezers 100, 101, 102, . . . , 10n. According to one embodiment, the predetermined freezing profiles maybe transmitted to the plurality of freezers at substantially the sametime. By transmitting the predetermined freezing profiles to theplurality of freezers, consistency can be increased, since the instancesof human error when inputting the predetermined freezing profiles isreduced.

When a sample is required to be frozen at one of the plurality offreezers, the user 120, 121, 122, . . . , 12 n at the freezer is onlyrequired to select the appropriate predetermined freezing profile, froma plurality of predetermined freezing profiles, via the user interface14, such as a touch screen, at the freezer. The user 120, 121, 122, . .. , 12 n at the freezer is not required to manually enter thepredetermined freezing profile into the freezer. The user at the freezermay also be required to enter their user ID, via the user interface 14,before using the freezer. The user at the freezer may also be requiredto enter the sample ID, via the user interface 14, such as by using atouch screen, a bar code scanner when the sample ID is stored as a barcode, an imaging device when the sample ID is stored as a QR code etc.

Transmitting the predetermined freezing profiles to the plurality offreezers is also advantageous in that the user 140 at the remote server130, can then guarantee that each freezer is using the samepredetermined freezing profiles, when freezing the same sample. This isuseful when identifying anomalies in data gathered from a plurality offreezer all running the same predetermined freezing profiles.Furthermore, when a predetermined freezing profile is updated by theskilled scientist, for example as a result of new data becomingavailable, an updated version of the predetermined freezing profile canbe distributed to the plurality of freezers from the remote server,enhancing consistency across the network of freezers. According to oneembodiment, the updated predetermined freezing profiles may betransmitted to the plurality of freezers at substantially the same time.

The predetermined freezing profiles may be provided to the plurality offreezers as a graph, such as illustrated in FIG. 2 , or as a set ofinstructions. An exemplary set of instructions for the graph illustratedin FIG. 2 could be represented as:

STEP TIME (minutes) TYPE TEMPERATURE (° C.) 1 t = 0 — 22° C. 2 t = 0 tot = 20 Ramp from 22° C. to 4° C. 3 t = 20 to t = 58 Dwell at 4° C. 4 t =58 to t = 154 Ramp from 4° C. to −92° C. 5 t = 154 to t = 165 Ramp from−92° C. to −100° C. 6 t = 165 to t = 180 Dwell at −100° C.

When a predetermined freezing profile is selected at one of theplurality of freezers, the detected sensor data, freezer data, sampledata and/or user data which relates to the freezing of a sample inaccordance with the freezing profile is transmitted from the freezer tothe remote server 130. The data may be transferred from the freezer tothe remote server continuously, periodically or at the end of thefreezing cycle, as required. Accordingly, the remote server may receivethe data in near-real time. The remote server 130 stores the receiveddata in the data store 56.

The detected freezing data, which relates to the freezing of a sample inaccordance with a predetermined freezing profile, may be transferredfrom the freezer to the remote server 130 as a graph, such asillustrated in FIG. 4 . Alternatively, the detected freezing data, whichrelates to the freezing of a sample in accordance with a predeterminedfreezing profile, may be transferred from the freezer to the remoteserver 130 as a plurality of data logs. In another alternative, thedetected freezing data, which relates to the freezing of a sample inaccordance with a predetermined freezing profile, may be transferredfrom the freezer to the remote server 130 as a combination of graph(s)and/or a plurality of data logs.

When the remote server 130 receives a plurality of detected data logs,the remote server may generate an actual freezing graph from theplurality of data logs representing the freezing of the sample, such asthe graph illustrated in FIG. 4 .

A user 140 can access the received freezing data, which relates to thefreezing of a sample in accordance with a predetermined freezingprofile, at the remote server 130. The server 130 can provide the userwith the data from one or more freezers and/or one or more freezes. Forexample, a clinical trial may involve the freezing of a plurality ofsamples (of the same type) at a plurality of different freezers, all thefreezers using the same freezing profile. The received data, regardingthe plurality of freezes at a plurality of different freezers can thenbe presented to the user 140 in a user-friendly format. For example, theremote server 130 may generate a “freezing consistency report” from thereceived data. A “freezing consistency report” may provide the receivedfreezing data, received from the plurality of freezers, on one graph,such that it easy for a user to look across a range of differentfreezers and/or freezes and to compare, for example, minimum, maximumand average freeze times. In addition, a tight grouping may indicatevery consistent performance, whereas a wide spread may suggest somethingwas not being well controlled. Furthermore, any anomalies in thereceived freezing data can be easily identified by a user. The “freezingconsistency report” may also provide drop down filters so the user 140can further tighten the analysis e.g. to a single freezer, a singleuser, a single freezing profile etc. The ability to store the datareceived from a plurality of different freezers regarding a plurality ofdifferent freezes is advantageous as anomalies can be identified quicklyby a remote user. This is particularly beneficial for a user running aclinical trial, where previously a remote user would not have receivedthe data, for maybe weeks after the freeze, and/or would not havereceived the same quantity or quality of data, since previously only thesensor freezing data would have been provided.

According to one embodiment, the remote server 130 may annotate thereceived freezing data with “observations”. FIG. 8 illustrates an actualfreezing graph which the remote sever has generated from the receiveddata logs, and annotated with observations. The observations aregenerated by the remote server based on the data received from thefreezer. For example, with reference to FIG. 8 , the observation is “lidclosed”. The observation “lid closed” is determined from the receivedsensor data, for example, the door sensor data indicates that the doorsensor detected that the lid was closed, at time 01:43. Therefore, theremote server adds an observation “lid closed” at time 01:43 to thereceived freezing data.

In addition, the operator of the freezer, user 120, 121, 122, . . . , 12n, may create user observations and add notes, which are transferredfrom the freezer to the remote server 130. For example, when abiological sample is being frozen as part of a clinical trial, the user120, 121, 122, . . . , 12 n may add an observation, such as the timethat the sample was obtained from the patient, prior to the sample beingfrozen. These user observations are added at the freezer via the userinterface 14 and transferred to the remote server 130 as user datatogether with the other data which relates to the freezing of a samplein accordance with a predetermined freezing profile.

The received sensor data, freezer data, sample data and/or user data,which relates to the freezing of the sample in accordance with thefreezing profile, received at the remote server 130 can also be analysedin order to perform checks on the freezing process. For example, apredetermined freezing profile may require approximately 500 joules ofenergy to complete the freeze. When five of the freezers transfer dataindicating that they completed the freezing cycle in accordance with thepredetermined freezing profile using approximately 500 joules of energy,but one of the freezers transfers data indicating that it completed thefreezing cycle in accordance with the predetermined freezing profileusing 800 joules of energy, then it is possible to determine that anunknown event has occurred at that freezer, and further investigation isrequired. Previously it would not have been possible to compare suchdata and therefore, it would not have been possible to identify that anunknown event has occurred at the freezer which required furtherinvestigation.

According to one embodiment, the remote server may provide a suggestionas to what the event might be. For example, if additional power wasrequired to freeze the sample, then the server may suggest that thesample was of a size greater than that indicated for the selectedpredetermined freezing profile. According to one embodiment, the servermay provide alerts to a user. For example, most freezers comprise analarm to indicate to a user in the proximity of the freezer when a doorhas been left open. However, the remote server may also provide alertsdirect to a user, such as to a user's mobile device, when an event hasoccurred at the freezer. The alerts may be visual and/or audible alerts.

The cryogenic freezing of a sample is normally only one stage in theprocessing of a biological sample. FIG. 9 illustrates schematically asimple overview of the processing of a biological sample. As illustratedin FIG. 9 , the sample is obtained at step S200. The sample is thenfrozen at a controlled-rate, in accordance with a predetermined freezingprofile, at step S210, such as described above. Following freezing, thesample may be required to be stored and/or transported to anotherlocation at step S220 prior to controlled thawing at step S230, andutilisation at step S240. In between freezing and thawing, the sample isrequired to be cryogenically stored whilst being transported, ifrequired to another location. It is important to the integrity of thesample that the sample be kept in predetermined conditions at all ofthese stages.

Data recorded at each of these stages may be transferred to the remoteserver 130, either continuously, periodically or at the end of eachstage in the process, as required.

A thawing machine, for example, a VIA THAW machine by ASYMPTOTE may beused to provide controlled thawing of a sample. FIG. 10 schematicallyillustrates a thawing machine 350. As can be seen from FIG. 10 , athawing machine 350 comprises a thawing compartment 370, for example, awater bath, within which a sample 30 to be thawed may be provided,coupled to a heating unit 380. The thawing machine 350 also comprises acontrol module 360 comprising at least one processor 361 coupled to atleast one memory 363, at least one user interface 363, at least onecommunications interface 365, at least one data store 364, and at leastone sensor 366, 367, 368, . . . 36 n. The thawing machine 350 may alsocomprises other elements which are not illustrated.

The memory 363 may comprise program memory for storing computer programcode to control the heating unit 380 in order to thaw a sample 30provided in the thawing compartment 370, as described herein, andworking memory for storing data, programs, or instructions received orprocessed by the processor 361. The memory 363 and/or the data store 364may comprise a volatile memory such as random access memory (RAM), foruse as temporary memory. Additionally or alternatively, the memory 363and data store 364 may comprise non-volatile memory such as Flash, readonly memory (ROM) or electrically erasable programmable ROM (EEPROM).

The processor 361 may comprise processing logic to process data (forexample, data received from the sensors 366, 367, 368, . . . 36 n,programs, instructions received from a user via the user interface 363etc.) and generate output signals in response to the processing. Thecontrol module 360 may comprise any suitable circuitry or logic, andmay, for example, comprise any one or more of the following: a fieldprogrammable gate array (FPGA), system on chip device, microprocessordevice, microcontroller, and one or more integrated circuits. Thecontrol module 360 is coupled to the heating unit 380 in order tocontrol the temperature in the thawing compartment 370.

The user interfaces 363 may be one or more of a computer screen, a touchscreen, a keyboard, a mouse, speakers, a bar code scanner, a fingerprintscanner etc.

The communication module 365 may be configured to receive data or datasignals from one or more external devices (such as a remote server asdescribed herein). The communication module 365 may be a communicationinterface or unit. The communication module 365 may be configured toreceive data via a wired or wireless network, such as the internet. Thecommunication module 365 may also be configured to transmit data or datasignals to one or more external devices (such as a remote server) via awired or wireless network, such as the internet.

The data store 364 may be configured to store data from the sensors 366,367, 368, . . . 36 n. The data store 364 may be coupled to the at leastone communication module 365 and the at least one processor 361.

The components of the control module 360 may be a combination ofhardware and software components, all software components, or allhardware components.

Cryogenic thawing machines, such as illustrated in FIG. 10 , thaw asample in accordance with a thawing profile. Each sample requires itsown thawing profile to be determined by a skilled scientist. As with thefreezing profile, each thawing profile is determined based on numerousfactors such as the composition of the sample, the size (weight) of thesample, the amount of cryoprotectant added to the sample prior tofreezing, the container within which the sample is provided etc.

A thawing profile is normally simpler than a freezing profile andspecifies, for example: a heating unit temperature; container type;container size (ml); what temperature will trigger a “too warm” alertwhen a sample is loaded into the thawing machine for thawing; what timewill trigger a “too long” alert when a sample has taken too long tothaw. According to one embodiment, a thawing profile is defined as alist of instructions. FIG. 11 illustrates an exemplary thawing profile.

FIG. 12 illustrates an exemplary detected thawing sample temperature(continuous line) together with the heater temperature (dotted line).

A thawing profile comprises a set of instructions, regardless of format,which are input into a thawing machine, and which defines the rate atwhich a sample heats up during a thawing cycle. A thawing cycle beginsat time t=0 minutes, when a sample is placed in a thawing machine. Athawing cycle ends when the sample has reached the desired temperature,which in most instances is just above the sample's melting point.

As stated above, the thawing machine 350 comprises at least one sensor366, 367, 368, . . . 36 n. One, or more, of the sensors 366, 367, 368, .. . 36 n comprises a temperature sensor provided to monitor thetemperature within the thawing compartment 370 during a thawing cycle.The temperature sensors also detect the temperature at the heating unit380 during a thawing cycle. The detected temperatures are stored in thedata store 364 together with the location of the sensor and/or a sensorID and the time at which the temperature was sensed.

In addition to detecting the temperatures within the thawing machineduring a thawing cycle, one or more sensors 366, 367, 368, . . . 36 nmay be provided to detect the external temperature at the thawingmachine during a thawing cycle. In addition, one or more sensors may beprovided to detect when the door of the thawing machine is opened, whenthe door of the thawing machine is closed, the time and date at whichthe door is opened/closed, and/or the duration of time the door wasopen.

According to one embodiment, the sensors 366, 367, 368, . . . 36 ndetect continuously during a thawing cycle. According to anotherembodiment, the sensors 366, 367, 368, . . . 36 n detect periodicallyduring a thawing cycle.

The sensor data detected by the sensors 366, 367, 368, . . . 36 nrelates to the thawing of a sample in accordance with a thawing profile.The sensor data detected by the sensors 366, 367, 368, . . . 36 n maycomprise one or more of: the temperature, at one or more locationswithin the thawing compartment during a thawing cycle; the temperatureat the heating unit during a thawing cycle; the external temperature atthe thawing machine during a thawing cycle; thawing machine door data,such as when the door of the thawing machine is opened and/or closedduring a thawing cycle. For each detection, the time and date of thedetection is also recorded together with an indication of the detectingsensor.

In addition to the sensor data detected by the sensors 366, 367, 368, .. . 36 n, the control module 360 is also capable of detecting andstoring other data which relates to the thawing of the sample inaccordance with the thawing profile. The other data may comprise thawingmachine data and/or sample data and/or user data etc. The control module360 may store thawing machine data such as: a thawing machineidentifier; thawing machine energy consumption (for example, the energyconsumed by the thawing machine during a thawing cycle and/or the energyconsumed by different components of the thawing machine during a thawingcycle); thawing machine location (for example, the actual location ofthe thawing machine and/or the thawing machines IP address); thawingmachine alarm data, such as whether an alarm was activated at thethawing machine (for example, a sample too warm alarm) and/or whetherany action was taken in response to the alarm. The control module 360may store sample data such as: a sample identifier; sample compositiondata (such as information regarding the composition of the sample);sample size/weight data (such as information regarding the size/weightof the sample); sample container data (such as information regarding thesample container; the predetermined thawing profile; sample thaw date(such as the date the sample was thawed in accordance with the thawingprofile); sample thaw time (such as the start time of the thawing cycle,the end time the thawing cycle and/or the duration of the thawingcycle). The control module 10 may store user data such as: a useridentifier; user observations, discussed in further detail below.

The sensor data detected by the sensors 366, 367, 368, . . . 36 n, aswell as the thawing machine data and/or sample data and/or user data,all of which relates to the thawing of a sample in accordance with athawing profile, is of interest to a user. However, the user may not beat the location of the thawing machine, for example, because the userrequires data from multiple thawing machines, or because the user isperforming a clinical trial which requires data from multiple locations.Therefore, the communication module 365 may be used to transfer thedetected data from the thawing machine to a remote server 50, such asdescribed above and illustrated in FIG. 6 .

FIG. 13 illustrates schematically a system for monitoring one or morethawing machines. A plurality of thawing machines 300, 301, 302, . . . ,30 n are illustrated in FIG. 13 . Each of the plurality of thawingmachines 300, 301, 302, . . . , 30 n may be provided at the same, or atdifferent locations from the other thawing machines. In addition, eachof the plurality of thawing machines 300, 301, 302, . . . , 30 n may beprovided at the same location as a freezer, or at different locationfrom a freezer. Each thawing machine 300, 301, 302, . . . , 30 n may beoperated by a human operator (users 320, 321, 322, . . . , 32 n). Inaddition, each thawing machine 300, 301, 302, . . . , 30 n iscommunicatively coupled to a remote server 130.

The remote server 130 is communicatively coupled to at least one thawingmachine. According to one embodiment, the communication module 60 isused to connect the remote server to at least one thawing machine over anetwork, such as the Internet. The connection may be wired or wireless.The plurality of thawing machines 300, 301, 302, . . . , 30 n are ableto exchange data with the remote server 130. For example, the pluralityof thawing machines 300, 301, 302, . . . , 30 n are capable oftransmitting data to the remote server 130, and the remote server 130 iscapable of receiving the transmitted data from the plurality of thawingmachines 300, 301, 302, . . . , 30 n. In addition, the remote server 130is capable of transmitting data to the plurality of thawing machines300, 301, 302, . . . , 30 n, and the plurality of thawing machines 300,301, 302, . . . , 30 n are capable of receiving the transmitted datafrom the remote server 130.

According to one embodiment, the data which is transferred between thethawing machine and the server is encrypted, for example, using aprivate/public key pair etc.

As stated above, the thawing profiles are predetermined by skilledscientists. The predetermined thawing profiles are provided togetherwith their associated criteria, such as the composition of the sample,the size of the sample, the amount of cryoprotectant to be added to thesample, the type of container in which the sample is to be provided etc.to the remote server 130. According to one embodiment, the remote server130 transmits the predetermined thawing profiles to the plurality ofthawing machines 300, 301, 302, . . . , 30 n. The predetermined thawingprofiles may be transmitted to the plurality of thawing machines 300,301, 302, . . . , 30 n at substantially the same time. When apredetermined thawing profile is updated by a skilled scientist, anupdated version of the predetermined thawing profile may be distributedto the plurality of thawing machines from the remote server. The updatedpredetermined thawing profiles may be transmitted to the plurality ofthawing machines at substantially the same time.

When a sample is required to be thawed at one of the plurality ofthawing machines, the user 320, 321, 322, . . . , 32 n at the thawingmachine is only required to select the appropriate predetermined thawingprofile, from a plurality of predetermined thawing profiles, via theuser interface 363, such as a touch screen, at the thawing machine. Theuser 320, 321, 322, . . . , 32 n at the thawing machine is not requiredto manually enter the predetermined thawing profile into the thawingmachine. The user 320, 321, 322, . . . , 32 n at the thawing machine mayalso be required to enter their user ID, via the user interface 363,before using the thawing machine. The user at the thawing machine mayalso be required to enter the sample ID, via the user interface 363,such as by using a touch screen, a bar code scanner when the sample IDis stored as a bar code, an imaging device when the sample ID is storedas a QR code etc., before using the thawing machine.

As is understood in the art, an actual thawing temperature achieved byeach thawing machine may vary from the predetermined thawing profile.Variations can occur as a result of numerous factors, such as theaccuracy of the preparation of the sample. For example, a predeterminedthawing profile may specify that thawing begins at the temperature atwhich the sample is frozen and/or stored (as appropriate). However, theactual sample will start thawing the moment it is removed from itsstorage unit, therefore, the actual temperature of the sample when itenters the thawing machine may be different from that defined in thethawing profile. This is particularly evident when the transfer of thesample from the storage device to the thawing machine is notinstantaneous. For example, when a sample is being kept at −196° C., itwill start thawing very quickly when removed from its storageenvironment to room temperature prior to been provided in the thawingmachine. Such variations from the specified criteria of thepredetermined thawing profile may result in detected thawing data, suchas the sample temperature, which is different from the predeterminedthawing profile.

When a predetermined thawing profile is selected at one of the pluralityof thawing machines, and a sample is thawed in accordance with theselected predetermined thawing profile, the detected sensor data,thawing machine data, sample data and/or user data, which relates to thethawing of the sample in accordance with the predetermined thawingprofile, is transmitted from the thawing machine to the remote server130. The data may be transferred from the thawing machine to the remoteserver continuously, periodically or at the end of the thawing cycle, asrequired. Accordingly, the remote server may receive the data innear-real time. The remote server 130 stores the received data in thedata store 56.

The detected thawing data, which relates to the thawing of a sample inaccordance with the predetermined thawing profile, may be transferredfrom the thawing machine to the remote server 130 as a graph, such asillustrated in FIG. 12 . Alternatively, the detected thawing data, whichrelates to the thawing of a sample in accordance with the predeterminedthawing profile, may be transferred from the thawing machine to theremote server 130 as a plurality of data logs of what actually happenedwhilst the sample was being thawed. In another alternative, the detectedthawing data, which relates to the thawing of a sample in accordancewith the predetermined thawing profile, may be transferred from thethawing machine to the remote server 130 as a combination of graph(s)and/or a plurality of data logs.

When the remote server 130 receives a plurality of data logs, the remoteserver may generate an actual thawing graph from the plurality of datalogs, representing the thawing of the sample, such as the graphillustrated in FIG. 12 .

A user 140 can then access the received data, which relates to thethawing of a sample in accordance with the predetermined thawingprofile, at the remote server 130. The server 130 can provide the userwith the data from one or more thawing machines and/or one or morethaws. For example, a clinical trial may involve the thawing of aplurality of samples (of the same type) at a plurality of differentthawing machines, all of the thawing machines using the samepredetermined thawing profile. The data regarding the plurality of thawsat the plurality of different thawing machines can then be presented tothe user 140 in a user-friendly format. For example, the remote server130 may generate a “thawing consistency report” from the received data.A “thawing consistency report” may provide the received thawing data,received from the plurality of thawing machines, on one graph, such thatit easy for a user to look across a range of different thawing machinesand/or thaws and to compare, for example, minimum, maximum and averagethaw times. In addition, a tight grouping may indicate very consistentperformance, whereas a wide spread may suggest something was not beingwell controlled. Furthermore, any anomalies in the received thawing datamay be easily identified by a user. The “thawing consistency report” mayalso provide drop down filters so the user can further tighten theanalysis e.g. to a single thawing machine, a single user, a singlethawing profile etc. The ability to store the data received from aplurality of different thawing machines regarding a plurality ofdifferent thaws is advantageous as anomalies can be identified quicklyby a remote user. This is particularly beneficial for a user running aclinical trial, where previously a remote user would not have receivedthe data, for maybe weeks after the thaw, and/or would not have receivedthe same quantity of data, since previously only the detectedtemperature data may be provided.

According to one embodiment, the remote server 130 may annotate thereceived thawing data with “observations”. FIG. 14 illustrates adetected thawing sample temperature annotated with observations. Theobservations are generated based on the data received from the thawingmachine. For example, with reference to FIG. 14 , the observation is“User loaded the vial”. The observation “User loaded the vial” isdetermined from the received sensor data, for example, the time at whichthe thawing machine sensed that a vial had been added.

In addition, the operator of the thawing machine, user 320, 321, 322, .. . , 32 n, may also create user observations and add notes, which arealso transferred from the thawing machine to the remote server 130, asuser data. For example, when a biological sample is being thawed as partof a clinical trial, the user 320, 321, 322, . . . , 32 n may addobservations, such as the time that the sample was administered to thepatient, following thawing of the sample. These user observations areadded at the thawing machine via the user interface and transferred tothe remote server 130. According to another embodiment, userobservations may be added via an application, to the remote server 130.

The received sensor data, thawing machine data, sample data and/or userdata, which relates to the thawing of the sample in accordance with thepredetermined thawing profile received at the remote server 130 can beanalysed in order to perform checks on the thawing process. For example,a predetermined thawing profile may require approximately 500 joules ofenergy to complete the thaw. When five of the thawing machines transferdata indicating that they completed the predetermined thawing profileusing approximately 500 joules of energy, but one of the thawingmachines transfers data indicating that it completed the predeterminedthawing profile using 800 joules of energy, then it is possible todetermine that an unknown event has occurred at that thawing machine,and further investigation is required. Previously it would not have beenpossible to compare such data and therefore, it would not have beenpossible to identify that an unknown event has occurred at the thawingmachine which required further investigation.

FIG. 17 illustrates a graph of two different sets of detected thawingtemperatures, both of which relate to the thawing of a sample inaccordance with the same predetermined thawing profile. The twodifferent sets of thawing temperatures were recorded by temperaturesensors at a thawing machine and were received at the remote server 130.The solid line indicates the temperatures detected whilst thawing asample having a 10% aqueous DMSO solution, and the dashed line indicatesthe temperatures detected whilst thawing a sample having an‘incorrectly’ formulated solution, where the DMSO was not added. Itwould be apparent to any skilled person in the field when viewing thegraph of FIG. 17 , that due to the different warming rates—as well asthe much higher temperature plateau which is indicative of the meltingpoint of a solution—that the ‘incorrectly’ formulated solution deviatedfrom a correct formulation. The ability to compare data from a pluralityof different thawing machines and/or a plurality of different thaws isadvantageous since incorrect thaws can be identified quickly, which canact as a quality control of the solutions. In addition, the datareceived at the server 130 can be referred to immediately after a thaw,and may also be referred back to at a later time, since the data issaved at the server.

According to one embodiment, the remote server may provide a suggestionas to what the cause of a deviation from a predetermined thawing profileand/or a deviation between data detected using the same predeterminedthawing profile might be. For example, when the thawing temperatureplateaus are different, then the remote server may indicate that thefreezing solution has been incorrectly formulated.

According to one embodiment, the remote server may also be able toprovide alerts to a user. For example, the thawing machine may comprisean alarm to indicate to a user in the proximity of the thawing machinethat the added vial is too hot. However, the remote server may also beable to provide alerts direct to a user, such as to users mobile device,when an event has occurred at a thawing machine. The alerts may bevisual and/or audible alerts.

Further quality control information and other information can bedetermined through differential thermal analysis (DTA) on the detecteddata which is transmitted to the remote server. DTA can be performed onthe data received from freezers, thawing machines and transportationdevices (described below). The following example refers to data receivedfrom a freezer. As described above, a freezer transmits detected sensorsdata (such as the detected temperature of the sample plate during thefreezing cycle), and/or freezer data (such as the voltage supplied tothe freezer during the freezing cycle) and/or sample data (such as theselected predetermined freezing profile) and/or user data etc. By, forexample, integrating the detected power curves shown in FIG. 18 , it ispossible to calculate the energy required for the freezing cycle.

From the measured power-time curve for the sample freezing exampleillustrated in FIG. 18 , it is possible to relate the measured powerconsumed during the freezing cycle (the solid line) to the expectedpower removed from the sample during the freezing cycle (the dashedline). After nucleation and during the bulk of the phase change there isa large increase in power required to maintain the linear rate oftemperature reduction (power is illustrated with a solid line in FIG. 18) which may be recorded and transmitted to the remote server. Beforenucleation and also after the bulk of the freezing, FIG. 18 shows thatthe measured power is increasing approximately linearly with time—thisis how the dashed expected power line is derived. However, it is knownthat before nucleation the rate of heat removal from a sample (withconstant mass and specific heat capacity) must be constant when thetemperature is being reduced linearly. This means that the approximatelylinear power, prior to nucleation must represent a constant “baseline”rate of heat removal from the sample (dashed line FIG. 18 ), togetherwith an additional linearly increasing power requirement of the freezerto supply the plate itself and any losses in the system. This recordedpower data profile before and after bulk ice formation (dashed line inFIG. 18 ) can readily be subtracted from the measured power beingremoved from the sample (solid line in FIG. 18 ), and obtain directestimates of the changes in heat release during freezing.

To do this for this, for example, the regions between the curves in FIG.18 can be integrated, using Simpson's rule or any other appropriatemethod clear to a skilled person, between nucleation, where the linesdiverge, and the point where the lines re-join.

This data can be used to determine the total amount of ice formed, andif different from a predicted or separate control sample would indicateto the skilled person that for example, either volume or composition ofthe freeing sample was incorrect. In addition, the large increase inpower which is recorded at the freezer and transmitted to the remoteserver indicates when ice nucleated during the freezing cycle and atwhat temperature.

Additionally, according to another example, the power recorded at athawing machine and transmitted to the remote server during a thawingcycle may be used to determine the heat capacity of the solution, whichcan be compared with known values for quality control.

Returning to FIG. 9 , following freezing, a sample may be required to bestored and/or transported to another location prior to thawing. Tosimplify tracking of each sample, each sample may be provided with aunique identifier (sample ID), such as a bar code, a QR code or anidentification code, which may be any combination of numbers and/orletters. When a sample is frozen, it's sample ID may be input by a user120, 121, 122, . . . , 12 n at the freezer 100, 101, 102, . . . , 10 n.For example, when the sample ID is a bar code, then the user may scanthe bar code prior to freezing the sample using a bar code scanner. Thesample ID is then associated with the predetermined freezing profilewhich is selected by the user 120, 121, 122, . . . , 12 n, the detectedsensor data, the freezer data, the sample data and/or the user data,which relates to the freezing of a sample in accordance with thepredetermined freezing profile, as discussed above.

In addition, when a sample is to be thawed, it's sample ID may be inputby a user 320, 321, 322, . . . , 32 n at the thawing machine 300, 301,302, . . . , 30 n. For example, when the sample ID is a bar code, thenthe user may scan the bar code prior to thawing the sample using a barcode scanner. The sample ID is then associated with the predeterminedthawing profile which is selected by the user 320, 321, 322, . . . , 32n, the detected sensor data, the thawing machine data, the sample dataand/or the user data, which relates to the thawing of a sample inaccordance with the predetermined thawing profile, as discussed above.

It is possible for a user 140 of the remote server to search for allentries associated with a specific sample ID. The user 140 is then ableto track the sample, from freezing to thawing.

The remote server is capable of transmitting a predeterminedtransportation profile to a transportation device which transports (andstores) a sample following cryogenic freezing to a different location.As with a thawing profile, a transportation profile is normally simplerthan a freezing profile and specifies, for example: a temperature atwhich the sample is to be stored; container type; container size (ml); aminimum and maximum humidity for the sample; a minimum and maximum gforce for the sample; what temperature will trigger a “too warm” alert;what temperature will trigger a “too cold” alert; what time will triggera “too long” alert when a sample has been stored for too long etc.According to one embodiment, a transportation profile is defined as alist of instructions.

A user at a transportation device is only required to select theappropriate predetermined transportation profile, from a plurality ofpredetermined transportation profiles, via the user interface 14, suchas a touch screen, at the transportation device. The user at thetransportation device may also be required to enter their user ID, viathe user interface 14, before using the transportation device. The userat the transportation device may also be required to enter the sampleID, via the user interface 14, such as by using a bar code scanner etc.,before using the transportation device.

The remote server is also capable of receiving data from atransportation device which stores and transports a sample followingcryogenic freezing. FIG. 15 schematically illustrates a cryogenictransportation device 500. A cryogenic transportation device 500comprises a portable power supply 550, such as a battery, and/or mayalso be connected to a power supply provided in a transportationvehicle.

As can be seen from FIG. 15 , a transportation device 500 comprises astorage compartment 570, within which a sample 30 is provided, coupledto a heating unit 580 and a heat removal unit 590. The storage device isrequired to keep the sample at a constant temperature. Thetransportation device 500 also comprises a control module 560 comprisingat least one processor 561 coupled to at least one memory 563, at leastone user interface 563, at least one communications interface 565, atleast one data store 564, at least one sensor 566, 567, 568, . . . 56 n,and at least one location detection module 540. The storage device 500may also comprises other elements which are not illustrated.

The memory 563 may comprise program memory for storing computer programcode to control the heating unit 580 and the heat removal unit 590 inorder to maintain the sample 30 at a constant temperature in the storagecompartment 570, and working memory for storing data, programs, orinstructions received or processed by the processor 561. The memory 563and/or the data store 564 may comprise a volatile memory such as randomaccess memory (RAM), for use as temporary memory. Additionally oralternatively, the memory 563 and data store 564 may comprisenon-volatile memory such as Flash, read only memory (ROM) orelectrically erasable programmable ROM (EEPROM).

The processor 561 may comprise processing logic to process data (forexample, data received from the sensors 566, 567, 568, . . . 56 n, thelocation detection module 540, programs, instructions received from auser via the user interface 563 etc.) and generate output signals inresponse to the processing. The control module 560 may comprise anysuitable circuitry or logic, and may, for example, comprise any one ormore of the following: a field programmable gate array (FPGA), system onchip device, microprocessor device, microcontroller, and one or moreintegrated circuits. The control module 560 is coupled to the heatingunit 580 and the heat removal unit 590 in order to control thetemperature in the storage compartment 570.

The user interfaces 563 may be one or more of a computer screen, a touchscreen, a keyboard, a mouse, speakers, a bar code scanner, a fingerprintscanner etc.

The communication module 565 may be configured to receive data or datasignals from one or more external devices (such as a remote server asdescribed herein). The communication module 565 may be a communicationinterface or unit. The communication module may be configured to receivedata via a wired or wireless network, such as the internet. Thecommunication module may also be configured to transmit data or datasignals to one or more external devices (such as a remote server) via awired or wireless network, such as the internet.

The data store 564 may be configured to store data from the sensors 566,567, 568, . . . 56 n and the location detection module 540. The datastore 564 may be coupled to the at least one communication module 565and the at least one processor 561.

The location detection module 540 may be any device capable of detectingthe location of the transportation device 500, such as a GPS locationdevice.

The components of the control module 560 may be a combination ofhardware and software components, all software components, or allhardware components.

As stated above, the transportation device 500 comprises at least onesensor 566, 567, 568, . . . 56 n. One, or more of the sensors 566, 567,568, . . . 56 n comprise temperature sensors provided to monitor thetemperature within the storage compartment 570 during transportation.The detected temperatures are stored in the data store 564 together witha sensor ID and the time at which the temperature was sensed.

In addition to detecting the temperatures within the transportationdevice during storing, one or more sensors 566, 567, 568, . . . 56 n maybe provided to detect the external temperature at the transportationdevice 500. In addition, one or more sensors may be provided to detectwhen the door of the transportation device 500 is opened, when the doorof the transportation device 500 is closed, the time and date at whichthe door is opened/closed, and/or the duration of time the door wasopen. In addition, one, or more of the sensors 566, 567, 568, . . . 56 nmay comprise g force sensors provided to detect the g force applied tothe transportation device 500 during transportation. In addition, one,or more of the sensors 566, 567, 568, . . . 56 n may comprise humiditysensors provided to detect internal and/or external humidity at thetransportation device 500 during transportation. In addition, one ormore of the sensors 566, 567, 568, . . . 56 n may detect the orientationof the transportation device 500. In addition, one, or more of thesensors 566, 567, 568, . . . 56 n may detect the power supply at thetransportation device 500, for example, when the transportation device500 is connected to a vehicles power supply, when the transportationdevice 500 requires power form the portable power supply 550, when thetransportation device 500 is running out of power (for example when theportable power supply 550 has only 20% power left etc.).

According to one embodiment, the sensors 566, 567, 568, . . . 56 ndetect continuously during transportation. According to anotherembodiment, the sensors 566, 567, 568, . . . 56 n detect periodicallyduring transportation.

The sensor data detected by the sensors 566, 567, 568, . . . 56 nrelates to the transportation of a sample in accordance with the sampletransportation profile data. The transportation sensor data detected bythe sensors 566, 567, 568, . . . 56 n may comprise one or more of: thetemperature within the storage compartment; the external temperature atthe transportation device; transportation device door data, such as whenthe door of the transportation device is opened and/or closed duringstorage; g force at the transportation device; orientation of thetransportation device; internal and/or external humidity at thetransportation device; power connection; battery life. For eachdetection, the time and date of the detection is also recorded togetherwith an indication of the detecting sensor.

In addition to the sensor data detected by the sensors 566, 567, 568, .. . 56 n, the control module 560 is also capable of detecting andstoring other data which relates to the transportation of the sample.The other data may comprise transportation device data and/or sampledata and/or user data etc. The control module 560 may storetransportation device data such as: a transportation device identifier;transportation device energy consumption (such as the energy consumed bythe transportation device during storage and/or by different componentsof the transportation device during storage); the location oftransportation device (such as the actual location, for example GPScoordinates, of the transportation device); transportation device alarmdata, such as whether an alarm was activated at the transportationdevice (for example, a sample too warm alarm, and whether any action wastaken in response to the alarm); the power supply at the transportationdevice; the amount of power available at the transportation device (forexample remaining battery power). The control module 360 may storesample data such as: a sample identifier; information regarding thecomposition of the sample; information regarding the size/weight of thesample; information regarding the sample container; the predeterminedfreezing profile; the predetermined transportation profile data; thepredetermined thawing profile; the date the sample was frozen. Thecontrol module 560 may store user data such as: a user identifier; userobservations.

The data detected by the sensors 566, 567, 568, . . . 56 n, as well asthe other data, all of which relates to the transportation of a samplemay be transferred to a remote server 50, such as described above andillustrated in FIG. 6 , via the communication module 565 at thetransportation device.

FIG. 16 illustrates schematically a remote system for monitoring one ormore devices for use in the cryogenic processing of a sample. Asillustrated in FIG. 16 , the remote server 130 is configured to receivedata from a freezer 10 n regarding the freezing of a sample, to receivedata from a storage device 420 regarding the storage of the sample, toreceive data from a transportation device 440, when a sample is to betransported to a different location, regarding thestorage/transportation of the sample, and to receive data from a thawingmachine 30 n regarding the thawing of a sample. The data recorded ateach of these devices may be transferred to the remote server, eithercontinuously, periodically or at the end of each stage in the process asrequired. Although only one freezer 10 n, storage device 420,transportation device 440 and thawing machine 30 n is illustrated inFIG. 16 , the remote server 130 is capable of communicating with aplurality of freezers 10 n, a plurality of storage devices 420, aplurality of transportation devices 440 and a plurality of thawingmachine 30 n.

The remote server 130 is communicatively coupled to at least onetransportation device 440. According to one embodiment, thecommunication module 60 is used to connect the remote server to at leastone transportation device 440 over a network, such as the Internet. Theconnection may be wired or wireless. The plurality of transportationdevices are able to exchange data with the remote server 130. Forexample, the plurality of transportation devices are capable oftransmitting data to the remote server 130, and the remote server 130 iscapable of receiving the transmitted data from the plurality oftransportation devices. In addition, the remote server 130 is capable oftransmitting data to the plurality of transportation devices and theplurality of transportation devices are capable of receiving thetransmitted data from the remote server 130.

According to one embodiment, the data which is transferred between thetransportation device and the server is encrypted, for example, using aprivate/public key pair etc.

The transportation profiles are predetermined by skilled scientists. Thepredetermined transportation profiles are provided together with theirassociated criteria, such as the composition of the sample, the size ofthe sample, the amount of cryoprotectant DMSO to be added to the sample,the type of container in which the sample is to be provided etc. to theremote server 130. According to one embodiment, the remote server 130transmits the predetermined transportation profiles to a plurality oftransportation devices. The predetermined transportation profiles may betransmitted to the plurality of transportation devices at substantiallythe same time. When a predetermined transportation profile is updated bya skilled scientist, an updated version of the predeterminedtransportation profile can may be distributed to the plurality oftransportation devices from the remote server. The updated predeterminedtransportation profiles may be transmitted to the plurality oftransportation devices at substantially the same time.

When a sample is required to be transported, a user at thetransportation device is only required to select the appropriatepredetermined transportation profile, from a plurality of predeterminedtransportation profiles, via the user interface 563, such as a touchscreen, at the transportation device. The user at the transportationdevice is not required to manually enter the predeterminedtransportation profile into the transportation device. The user at thetransportation device may also be required to enter their user ID, viathe user interface 563, before using the transportation device. The userat the transportation device may also be required to enter the sampleID, via the user interface 563, such as by using a touch screen, a barcode scanner when the sample ID is stored as a bar code, an imagingdevice when the sample ID is stored as a QR code etc., before using thetransportation device.

As is understood in the art, an actual detected transportation data mayvary from the predetermined transportation profile.

When a predetermined transportation profile is selected at atransportation device, and a sample is transported in accordance withthe selected predetermined transportation profile, the detected sensordata, transportation device data, sample data and/or user data, whichrelates to the transportation of the sample in accordance with thepredetermined transportation profile, is transmitted from thetransportation device to the remote server 130. The data may betransferred from the transportation device to the remote servercontinuously or periodically, as required. Accordingly, the remoteserver may receive the data in near-real time. The remote server 130stores the received data in the data store 56.

The detected transportation data, which relates to the transportation ofa sample in accordance with the predetermined transportation profile,may be transferred from the transportation device to the remote server130 as a graph. Alternatively, the detected transportation data, whichrelates to the transportation of a sample in accordance with thepredetermined transportation profile, may be transferred from thetransportation device to the remote server 130 as a plurality of datalogs of what actually happened whilst the sample was beingtransportation. In another alternative, the detected transportationdata, which relates to the transportation of a sample in accordance withthe predetermined transportation profile, may be transferred from thetransportation device to the remote server 130 as a combination ofgraph(s) and/or a plurality of data logs.

When the remote server 130 receives a plurality of data logs, the remoteserver may generate an actual transportation graph from the plurality ofdata logs, representing the transportation of the sample in thetransportation device.

A user 140 can then access the received data, which relates to thetransportation of a sample in accordance with the predeterminedtransportation profile, at the remote server 130. The server 130 canprovide the user with the data from one or more transportation devicesand/or transportations. The data regarding the plurality oftransportations at the plurality of different transportation devices canthen be presented to the user 140 in a user-friendly format.

The freezer/thawing machine/transportation device transmits the data tothe remote server via the internet. According to one embodiment, thefreezer/thawing machine/transportation device retains the data in itslocal data store until receipt of the data by the remote server isconfirmed. This ensures that the data is not deleted until it has beensafely stored at the remote server, for example in the data store 56.The freezer/thawing machine/transportation device may then delete thedata if required. Whether the freezer/thawing machine/transportationdevice deletes the transmitted data will depend on the size of the datastore provided at the freezer/thawing machine/transportation device.According to one embodiment, the data is stored at the freezer/thawingmachine/transportation device for a predetermined period of time, suchas one week, one month, one year etc. prior to deletion.

A user 140 is then able to review the data received by the remote server130. The user 140 is also able to search the data based on criteria,such as the freezer ID, freezing profile, sample ID, thawing machine IDetc. For example, when examining a predetermined freezing profile, itmay appear that a better result is achieved by one freezer and/or user;or that one freezer always produces freezing profiles that deviate fromthe predetermined profile by a greater amount than the other freezers.It is then possible for the user 140 to further investigate thatfreezer, for example, it may appear that the freezer is not functioningcorrectly. However, without being able to compare the freezer's resultswith other freezers, this malfunction would not be immediately apparent.

The ability to compile the data as well as filter and organise the datafrom a plurality of devices and samples, increases the usability of thedata since further analysis can be performed which previously was notpossible or not practical. The server can also be used to generatereports and/or graphs as required by the user 140 and discussed above.

Since the server 130 is connected to the internet, the user 140 of theserver does not need to be at the server 130 in order to access thedata. This is particularly useful when clinical trials are being carriedout at several different locations. The data regarding each process(i.e. freezing/storing/transporting/thawing etc.) can be transferred innear real time to the user running the trial.

An example of a generated report, generated by the remote server, is areport which present the data from multiple freezes (using the samepredetermined freezing profile), or multiple thaws (using the samepredetermined thawing profile) in such a way as to make an anomalyobvious to the user. According to one embodiment, the data from multiplefreezes, or multiple thaws are provided on the same time v's temperaturegraph such that an anomaly is clearly visible to the user.

The user 140 is able to select the group for which each report is to begenerated. For example, the user may select: a plurality of freezer,selected using the freezer ID's; a plurality of thawing machines,selected using the thawing machine ID's; a plurality of freezes,selected using the predetermined freezing profile; a user ID's; aplurality of samples, selected using the sample ID's etc. It is alsopossible for the user 340 to select a group for which each report is tobe generated based on the country in which the machines are based,selected using the location ID; or all the devices owned by a particularcompany, selected using the device ID (freezer ID, thawing machine ID,transportation device ID etc.); or all the devices taking part in aparticular trial, selected using the device ID (freezer ID, thawingmachine ID, transportation device ID etc.).

Furthermore, since the remote server provides the predetermined freezingprofile, thawing profile and/or transportation profile to the freezers,thawing machines and/or transportation devices, it is possible to selecta group of devices to receive each specific profile, and differentdevices may receive different profiles/version of profiles based on auser selected criteria. For example, all devices belonging to the samecompany may receive a first predetermined profile, whereas all devicesbelonging to a different company may receive a different predeterminedprofile.

It is further possible for a user to create rules which are then appliedto an individual device, all the devices, or a subset of the devices asrequired by the user. An example, of such as rule predefined at theremote server, may be the thawing machine determines that the sample istoo warm when it was loaded, from the temperature data, and the thawingmachine generates a warning locally at the thawing machine, the rulemight be that the remote server also generates a task for a user toreview this log because it has an associated warning. Other examples ofrules are: if a freeze or thaw log is missing information like detailsof the sample being processed, the remote server generates a task for auser to add this information; a summary of the previous week's equipmentlogs is emailed to a specified user weekly at a set time; if any thawsare aborted or fail at thawing machines A, B or C, email User Yimmediately to warn them etc.

According to another embodiment, the remote server is also capable oftransmitting instructions to the freezer/thawing machine/transportationdevice as required. For example, the remote server may send instructionsto a freezer to begin cooling down in the early hours of the morning inorder to prepare for use when an operator gets into work.

According to another embodiment, the remote server is also capable ofgenerating and transmitting alerts, such as door open, temperature toohot/too cold etc. There may be an alarm which is active at the device.However, the server may also generate and transmit alerts to a user, forexample via a user's mobile device. The user's response to the alert mayalso be recorded, such as user cancelled action, user over rid the alarmetc.

According to another embodiment, the remote server may also be used toprompt a user at the freezer/thawing machine to perform a task—forexample, once a sample has defrosted, a user may be prompted by theremote server to remove the sample from the thawing machine. This may bein addition to alerts set at the freezer/thawing machine.

According to another embodiment, a user at the remote server may alsointeract with the remote server, for example, via a web page in order toadd observations and/or annotate observations regarding the receivedthawing, freezing or transport data logs. For example, the user may addan observation to explain an anomaly once it has been investigated.

According to another embodiment, the remote server may generateinvoices. For example, once a sample has been thawed for use, the remoteserver generates an invoice from the manufacture of the sample to theuser of the sample.

As will be appreciated by one skilled in the art, the present techniquesmay be embodied as a system, method or computer program product.Accordingly, the present techniques may take the form of an entirelyhardware embodiment, an entirely software embodiment, or an embodimentcombining software and hardware.

Furthermore, the present techniques may take the form of a computerprogram product embodied in a computer readable medium having computerreadable program code embodied thereon. The computer readable medium maybe a computer readable signal medium or a computer readable storagemedium. A computer readable medium may be, for example, but is notlimited to, an electronic, magnetic, optical, electromagnetic, infrared,or semiconductor system, apparatus, or device, or any suitablecombination of the foregoing.

Computer program code for carrying out operations of the presenttechniques may be written in any combination of one or more programminglanguages, including object oriented programming languages andconventional procedural programming languages.

For example, program code for carrying out operations of the presenttechniques may comprise source, object or executable code in aconventional programming language (interpreted or compiled) such as C,or assembly code, code for setting up or controlling an ASIC(Application Specific Integrated Circuit) or FPGA (Field ProgrammableGate Array), or code for a hardware description language such asVerilog™ or VHDL (Very high speed integrated circuit HardwareDescription Language).

Code components may be embodied as procedures, methods or the like, andmay comprise sub-components which may take the form of instructions orsequences of instructions at any of the levels of abstraction, from thedirect machine instructions of a native instruction set to high-levelcompiled or interpreted language constructs.

It will also be clear to one of skill in the art that all or part of alogical method according to the preferred embodiments of the presenttechniques may suitably be embodied in a logic apparatus comprisinglogic elements to perform the steps of the method, and that such logicelements may comprise components such as logic gates in, for example aprogrammable logic array or application-specific integrated circuit.Such a logic arrangement may further be embodied in enabling elementsfor temporarily or permanently establishing logic structures in such anarray or circuit using, for example, a virtual hardware descriptorlanguage, which may be stored and transmitted using fixed ortransmittable carrier media.

In one alternative, an embodiment of the present techniques may berealized in the form of a computer implemented method of deploying aservice comprising steps of deploying computer program code operable to,when deployed into a computer infrastructure or network and executedthereon, cause said computer system or network to perform all the stepsof the method.

In a further alternative, the preferred embodiment of the presenttechniques may be realized in the form of a data carrier havingfunctional data thereon, said functional data comprising functionalcomputer data structures to, when loaded into a computer system ornetwork and operated upon thereby, enable said computer system toperform all the steps of the method.

It will be clear to one skilled in the art that many improvements andmodifications can be made to the foregoing exemplary embodiments withoutdeparting from the scope of the present techniques.

The invention claimed is:
 1. A remote server for remotely monitoringcryogenic processing of a sample, the remote server configured to:transmit sample freezing profile data to at least one cryogenic freezer,and to receive from the at least one freezer detected freezer sensordata relating to the freezing of the sample in accordance with thesample freezing profile data, and to transmit the same sample freezingprofile data to the at least one cryogenic freezer; transmit samplethawing profile data to at least one thawing machine, and to receivefrom the at least one thawing machine detected thawing sensor datarelating to the thawing of the sample in accordance with the samplethawing profile data; and transmit sample transportation profile data toat least one transportation device, and to receive from the at least onetransportation device detected transportation sensor data relating tothe transportation of the sample in accordance with the sampletransportation profile data; and a data store configured to storereceived data; wherein the remote server is further configured to one orboth of transmit or receive a same predetermined sample transportationprofile data to or from the at least one transportation device.
 2. Theserver of claim 1, further configured to receive: from the at least onefreezer at least one of sample freezer data and/or user data, relatingto the freezing of the sample in accordance with the sample freezingprofile data; from the at least one thawing machine at least one ofdetected thawing machine data, sample thawing data and/or user data,relating to the thawing of the sample in accordance with the samplethawing profile data; and from the at least one transportation device atleast one of sample transportation data and/or user data, relating tothe transportation of the sample in accordance with the sampletransportation profile data.
 3. The server of claim 1, furtherconfigured to: transmit an update to the sample freezing profile data tothe at least one freezer; transmit an update to the sample thawingprofile data to the at least one thawing machine; and transmit an updateto the sample transportation profile data to the at least onetransportation device.
 4. The server of claim 1, further configured to:receive the detected data continuously, periodically or at an end of afreezing cycle from the at least one freezer; receive the detected datacontinuously, periodically or at an end of a thawing cycle from the atleast one thawing machine; and receive the detected data continuously orperiodically from the at least one transportation device.
 5. The serverof claim 1, further comprising a processor configured to generate: anactual freezing graph from the detected data received from the at leastone cryogenic freezer; an actual thawing graph from the detected datareceived from the at least one thawing machine; and an actualtransportation graph from the detected data received from the at leastone transportation device.
 6. The server of claim 1, further comprising:a processor configured to compare: the sample freezing profile data tothe detected data received from the at least one cryogenic freezer; thesample thawing profile data to the detected data received from the atleast one thawing machine; and the sample transportation profile data tothe detected data received from the at least one transportation device.7. The server of claim 5, further configured to: transmit the samplefreezing profile data to a plurality of cryogenic freezers; and whereinthe processor is further configured to compare the actual freezinggraphs generated for the plurality of freezers; transmit the samplethawing profile data to a plurality of thawing machines; and wherein theprocessor is further configured to compare the actual thawing graphsgenerated for the plurality of thawing machines; and transmit the sampletransportation profile data to a plurality of transportation devices;and wherein the processor is further configured to compare the actualtransportation graphs generated for the plurality of transportationdevices.
 8. The server of claim 1, further configured to: transmit thesample freezing profile data to a plurality of cryogenic freezers;transmit the sample thawing profile data to a plurality of thawingmachines; and transmit the sample transportation profile data to aplurality of transportation devices and further comprising: a processorconfigured to compare the detected data received from the plurality offreezers, thawing machines, and transportation devices.
 9. The server ofclaim 1, further configured to: transmit the sample freezing profiledata to a plurality of cryogenic freezers; transmit the sample thawingprofile data to a plurality of thawing machines; and transmit the sampletransportation profile data to a plurality of transportation devices,and further comprising a processor configured to: compare the detecteddata received from a group of freezers selected from the plurality offreezers; compare the detected data received from the plurality ofthawing machines; and compare the detected data received from a group oftransportation devices selected from the plurality of transportationdevices.
 10. The server of claim 1, wherein the freezer sensor datacomprises one or more of: at least one temperature within a freezercompartment of the at least one freezer during a freezing cycle; atemperature of the sample during a freezing cycle; an externaltemperature at the at least one freezer during a freezing cycle; orfreezer door data.
 11. The server of claim 1, wherein the thawing sensordata comprise one or more of: at least one temperature within a thawingcompartment of the at least one thawing machine during a thawing cycle;a temperature at a heating unit of the at least one thawing machineduring a thawing cycle; an external temperature at the at least onethawing machine during a thawing cycle; or thawing machine door data.12. The server of claim 1, wherein the transportation sensor datacomprise one or more of: at least one temperature within atransportation compartment of the at least one transportation devicesduring transportation; an external temperature at the at least onetransportation device; transportation device door data; g force at theat least one transportation device; orientation of the at least onetransportation device; internal and/or external humidity at the at leastone transportation device; power connection data; or battery life data.13. The server of claim 1, wherein: the freezer data comprises one ormore of: a freezer identifier; freezer energy consumption during afreezing cycle; freezer location; or freezer alarm data; the thawingmachine data comprises one or more of: a thawing machine identifier;thawing machine energy consumption during a thawing cycle; thawingmachine location; or thawing machine alarm data; and the transportationdevice data comprises one or more of: a transportation deviceidentifier; transportation device energy consumption data;transportation device location data; or transportation device alarmdata.
 14. The server of claim 1, wherein: the sample freezer datacomprises one or more of: a sample identifier; sample composition data;sample size data; sample container data; sample freezing profile data;sample freeze date; or sample freeze time; the sample thawing datacomprises one or more of: a sample identifier; sample composition data;sample size data; sample container data; sample thawing profile data;sample thaw date; or sample thaw time; and the sample transportationdata comprises one or more of: a sample identifier; sample compositiondata; sample size data; sample container data; sample freezing profiledata; sample transportation profile data; sample thawing profile data;sample transportation date.
 15. The server of claim 1, furtherconfigured to: receive user inputs relating to the freezing of thesample in accordance with the sample freezing profile data from the atleast one freezer; receive user inputs relating to the thawing of thesample in accordance with the sample thawing profile data from the atleast one thawing machine; and receive user inputs relating to thetransportation of the sample in accordance with the sampletransportation profile data from the at least one transportation device.16. The server of claim 1, further comprising: a processor configured togenerate observations based on the detected data, received from the atleast one freezer, the at least one thawing machines, and the at leastone transportation device.
 17. The server of claim 1, furthercomprising: a processor configured to generate alerts based on thedetected data received from the at least one freezer, the at least onethawing machines, and the at least one transportation device.
 18. Theserver of claim 1, further comprising: a processor configured to performdifferential thermal analysis (DTA) on the detected data.
 19. The serverof claim 18, wherein the processor is further configured to determinewhen the detected data deviates from a predicted or expected data. 20.The server of claim 1, further configured to one or both of transmit orreceive the same predetermined sample transportation profile data to orfrom the at least one transportation device.